Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Pharmacological modelling of dissociation and psychosis: an evaluation of the Clinician Administered Dissociative States Scale and Psychotomimetic States Inventory during nitrous oxide ('laughing gas')-induced anomalous states.

RATIONALE: A significant obstacle to an improved understanding of pathological dissociative and psychosis-like states is the lack of readily implemented pharmacological models of these experiences. Ketamine has dissociative and psychotomimetic effects but can be difficult to use outside of medical and clinical-research facilities. Alternatively, nitrous oxide (N2O) - like ketamine, a dissociative anaesthetic and NMDAR antagonist - has numerous properties that make it an attractive alternative for modelling dissociation and psychosis. However, development and testing of such pharmacological models relies on well-characterized measurement instruments. OBJECTIVES: To examine the factor structures of the Clinician Administered Dissociative States Scale (CADSS) and Psychotomimetic States Inventory (PSI) administered during N2O inhalation in healthy volunteers. METHODS: Secondary analyses of data pooled from three previous N2O studies with healthy volunteers. RESULTS: Effect sizes for N2O-induced dissociation and psychotomimesis were comparable to effects reported in experimental studies with sub-anaesthetic ketamine in healthy volunteers. Although, like ketamine, a three-factor representation of N2O-induced dissociation was confirmed, and a more parsimonious two-factor model might be more appropriate. Bayesian exploratory factor analysis suggested that N2O-induced psychosis-like symptoms were adequately represented by two negative and two positive symptom factors. Hierarchical cluster analysis indicated minimal item overlap between the CADSS and PSI. CONCLUSION: N2O and ketamine produce psychometrically similar dissociative states, although parallels in their psychosis-like effects remain to be determined. The CADSS and PSI tap largely non-overlapping experiences under N2O and we propose the use of both measures (or similar instruments) to comprehensively assess anomalous subjective states produced by dissociative NMDAR antagonists.

Opioids cause dissociated states of consciousness in C57BL/6J mice.

The electroencephalogram (EEG) provides an objective, neural correlate of consciousness. Opioid receptors modulate mammalian neuronal excitability, and this fact was used to characterize how opioids administered to mice alter EEG power and states of consciousness. The present study tested the hypothesis that antinociceptive doses of fentanyl, morphine, or buprenorphine differentially alter the EEG and states of sleep and wakefulness in adult, male C57BL/6J mice. Mice were anesthetized and implanted with telemeters that enabled wireless recordings of cortical EEG and electromyogram (EMG). After surgical recovery, EEG and EMG were used to objectively score states of consciousness as wakefulness, rapid eye movement (REM) sleep, or non-REM (NREM) sleep. Measures of EEG power (dB) were quantified as δ (0.5-4 Hz), θ (4-8 Hz), α (8-13 Hz), σ (12-15 Hz), ß (13-30 Hz), and γ (30-60 Hz). Compared with saline (control), fentanyl and morphine decreased NREM sleep, morphine eliminated REM sleep, and buprenorphine eliminated NREM sleep and REM sleep. Opioids significantly and differentially disrupted the temporal organization of sleep/wake states, altered specific EEG frequency bands, and caused dissociated states of consciousness. The results are discussed relative to the fact that opioids, pain, and sleep modulate interacting states of consciousness.NEW & NOTEWORTHY This study discovered that antinociceptive doses of fentanyl, morphine, and buprenorphine significantly and differentially disrupt EEG-defined states of consciousness in C57BL/6J mice. These data are noteworthy because: 1) buprenorphine is commonly used in medication-assisted therapy for opioid addiction, and 2) there is evidence that disordered sleep can promote addiction relapse. The results contribute to community phenotyping efforts by making publicly available all descriptive and inferential statistics from this study (Supplemental Tables S1-S8).

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions.

BACKGROUND: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use. METHODS: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed. RESULTS: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001). LIMITATIONS: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population. CONCLUSIONS: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation.

Managing dissociative symptoms following the use of esketamine nasal spray: a case report.

Patients with treatment-resistant depression (TRD) treated with esketamine nasal spray commonly experience transient symptoms of dissociation. Manifestations of dissociation, such as feelings of detachment from the environment, can cause considerable anxiety for patients. Nonpharmacologic interventions may help clinicians to manage associated anxiety and confusion due to dissociation following administration of esketamine nasal spray. We present the case of a 64-year-old woman with major depressive disorder who participated in a clinical trial evaluating the efficacy and safety of esketamine nasal spray in conjunction with an oral antidepressant for TRD. The patient received flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. On treatment day 1, the patient was administered 56 mg of esketamine nasal spray using two nasal spray devices (28 mg per device). Twenty minutes after the first esketamine nasal spray device was administered, the patient experienced a dissociative episode lasting 40 minutes that caused anxiety and confusion. The patient was encouraged to listen to music during treatment sessions, which resulted in notable improvement of her symptoms. Listening to music of choice immediately following esketamine nasal spray administration along with reassurance from staff may help manage confusion and anxiety associated with dissociation.

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review.

PURPOSE: Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects. METHODS: This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported Cmax values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman's method. RESULTS: A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine Tmax (r = - 0.87; p < 0.00001 for all). Ketamine Tmax strongly positively correlated with a change in dissociation ratings (r = - 0.96) and change in blood pressure (r = - 0.99; p < 0.00001 for all). CONCLUSION: Ketamine formulations that maximize first pass metabolism and delay Tmax will be better tolerated and safer than formulations which lack those characteristics.

Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials.

BACKGROUND: At ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR-gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. METHODS: Participants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. RESULTS: In the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected. CONCLUSIONS: Variation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect. TRIAL REGISTRATION: NCT02417064 and NCT02418585; www.clinicaltrials.gov.

Ascending-Dose Study of Controlled-Release Ketamine Tablets in Healthy Volunteers: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability.

Parenteral ketamine has fast-onset antidepressant and antianxiety effects; however, it causes dissociation, hypertension, and tachycardia shortly after dosing. Ketamine's antidepressant effects may be due to active metabolites rather than to ketamine itself. We hypothesized that oral controlled-release ketamine tablets would improve safety and tolerability compared with injected ketamine by reducing peak ketamine exposures compared with dosing by injection. In this randomized, placebo-controlled ascending-dose study, ketamine doses of 60, 120, or 240 mg or matching placebo (single dose followed by every-12-hours dosing for 5 doses) were given to 24 healthy volunteers. Pharmacokinetics, pharmacodynamics (brain-derived neurotropic factor), adverse events, and vital signs were assessed up to 72 hours. Drug release occurred over ∼10 hours, with most drug substance present as norketamine (∼90%). Area under the concentration-time curve and peak concentration were dose proportional. Elimination half-life was prolonged (7-9 hours) compared with published data from immediate-release oral formulations. There were no changes in blood pressure or heart rate after any dose. Mild dissociation was reported after 240 mg but not lower doses; mean dissociation ratings in this group were minimal (1-2/76). There were no clinically significant changes in ECGs or safety laboratory tests at any time. Compared with injected ketamine, oral controlled-release ketamine tablets did not increase blood pressure or heart rate, and only at doses of 240 mg was dissociation of mild intensity reported. Reducing and delaying ketamine peak concentration by oral dosing with controlled-release ketamine tablets improve this drug's tolerability for patients with depression/anxiety.

Safety and Tolerability of Ketamine Use in Treatment-Resistant Bipolar Depression Patients with Regard to Central Nervous System Symptomatology: Literature Review and Analysis.

The current psychopharmacological treatment approaches for major depression focus on monoaminergic interventions, which are ineffective in a large proportion of patients. Globally, treatment-resistant bipolar depression (TRBD) affects up to 33% of depressive patients receiving treatment. Certain needs are still unmet and require new approaches. Many studies are in favor of treatments with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, even in single use, whose effects emerge in minutes to hours post administration. However, little data are available on ketamine performance in TRBD patients with somatic comorbidities, including highly prevalent ones, i.e., cardiovascular disease (heart failure, hypertension, post-myocardial infarct, arrhythmias, etc.) diabetes, and obesity, and depression-associated comorbidities such as stroke, epilepsy, as well as in the elderly population. The literature shows that treatment with ketamine is efficacious and safe, and the majority of adverse drug reactions are mild and tend to mostly disappear within 30 min to 2 h of ketamine administration.

The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review.

OBJECTIVE: The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD). METHODS: Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports. RESULTS: Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS. CONCLUSIONS: Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.

Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study.

BACKGROUND: We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders. AIMS: The purpose of this study was to replicate our earlier report about ketamine's anxiolytic activity, using a more robust study design. METHODS: This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations. RESULTS: Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments. CONCLUSIONS: Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.

The Desire to Dissociate Scale: factor analysis, cross-cultural findings, and links to substance-induced dissociation.

BACKGROUND: Past research identified that a desire for dissociative experiences, rather than dissociative tendencies, mediate the relationship between early sexual abuse and problem drinking in college students. Desire to dissociate was conceptualized as a mechanism facilitating substance-induced dissociation or the use of substances to achieve dissociative-like experiences and was measured using a modified version of the Dissociative Experiences Scale-II. The validity and cross-cultural generalizability of the modified scale are not yet known. OBJECTIVES: The current study examined the psychometric properties of the modified scale, exploring findings across U.S. and Filipino college samples, and explored how the desire to dissociate construct related to other variables linked to substance-induced dissociation. Methods: Participants were recruited across two U.S. samples and one Filipino sample (N = 2404; 72% female). Instead of asking "how often do you experience" dissociative items, 14-items from the original scale were selected and individuals were asked "how often would you like to experience" items. RESULTS: Results supported the validity of the Desire to Dissociate Scale (DDS) with a bifactor model best fitting the data in U.S. and Filipino samples. The bifactor model identified that the DDS primarily measured a general 'desire to dissociate' factor and two specific factors comprised smaller portions of the variance. DDS scores were positively correlated with trauma-related and alcohol use variables including drinking to cope, variables conceptually consistent with theories of substance-induced dissociation. CONCLUSION: Clinical implications address avoidant coping patterns and differences in specific factor findings between U.S. and Filipino samples.

A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects.

Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p < .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users.Trial registration: ISRCTN Registry Identifier: ISRCTN24109245.

A Review of the Neurobiological Basis of Trauma-Related Dissociation and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response: a Transdiagnostic, Translational Approach.

Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treatment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense cascade model of dissociation and Mobb's threat detection model. In particular, we review neuroimaging studies highlighting alterations in functional connectivity of key brain regions associated with these models, including connectivity between the prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment modalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components of the defense cascade model.

Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans.

Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive-compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: Results from a randomized, controlled laboratory study.

Efforts to translate sub-anesthetic ketamine infusions into widespread clinical use have centered around developing medications with comparable neurobiological activity, but with attenuated psychoactive effects so as to minimize the risk of behavioral toxicity and abuse liability. Converging lines of research, however, suggest that some of the psychoactive effects of sub-anesthetic ketamine may have therapeutic potential. Here, we assess whether a subset of these effects - the so-called mystical-type experience - mediates the effect of ketamine on craving and cocaine use in cocaine dependent research volunteers. We found that ketamine leads to significantly greater acute mystical-type effects (by Hood Mysticism Scale: HMS), dissociation (by Clinician Administered Dissociative States Scale: CADSS), and near-death experience phenomena (by the Near-Death Experience Scale: NDES), relative to the active control midazolam. HMS score, but not the CADSS or NDES score, was found to mediate the effect of ketamine on global improvement (decreased cocaine use and craving) over the post-infusion period. This is the first controlled study to show that mystical-type phenomena, long considered to have therapeutic potential, may work to impact decision-making and behavior in a sustained manner. These data suggest that an important direction for medication development is the identification of ketamine-like pharmacotherapy that is selectively psychoactive (as opposed to free of experiential effects entirely), so that mystical-type perspectival shifts are more reliably produced and factors lending to abuse or behavioral impairment are minimized. Future research can further clarify the relationship between medication-occasioned mystical-type effects and clinical benefit for different disorders. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Effect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders.

Patients receiving ketamine for refractory depression and anxiety report dissociative symptoms in the first 60 min post-dose. The most commonly used instrument to assess this is the Clinician-Administered Dissociative States Scale (CADSS), developed based on the assessment of patients with dissociative symptoms. Its psychometric properties for ketamine-induced dissociation have not been reported. We evaluated these from a study using 0.25-1 mg/kg ketamine and midazolam (as an active control) in 18 patients with treatment-resistant anxiety. Dissociation ratings were increased by ketamine in a dose-dependent manner. In contrast, midazolam showed no effect on ratings of dissociation. For individual CADSS items, the magnitude of change and the ketamine dose at which changes were observed were not homogenous. The Cronbach alpha for the total scale was high (0.937), with acceptable item-rest correlations for almost all individual items. Purposefully removing items to maximise alpha did not lead to meaningful improvements. Acceptable internal consistency was still observed after removing items which lacked evidence of responsiveness at lower doses. The high Cronbach alpha values identified in this study suggests that the CADSS is an internally consistent instrument for evaluating ketamine-induced dissociation in clinical trials in anxiety, although it does not capture symptoms such as thought disorder.

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.